These authors contributed equally to this work.
Detection of Clinically Relevant Copy Number Variants with Whole-Exome Sequencing
Article first published online: 30 AUG 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 10, pages 1439–1448, October 2013
How to Cite
de Ligt, J., Boone, P. M., Pfundt, R., Vissers, L. E.L.M., Richmond, T., Geoghegan, J., O'Moore, K., de Leeuw, N., Shaw, C., Brunner, H. G., Lupski, J. R., Veltman, J. A. and Hehir-Kwa, J. Y. (2013), Detection of Clinically Relevant Copy Number Variants with Whole-Exome Sequencing. Hum. Mutat., 34: 1439–1448. doi: 10.1002/humu.22387
Contract grant sponsors: European Union TECHGENE Project (Health-F5-2009-223143); GEUVADIS Project (Health-F7-2010-261123); European Research Council (DENOVO 281964).
Communicated by Johan T. den Dunnen
- Issue published online: 18 SEP 2013
- Article first published online: 30 AUG 2013
- Accepted manuscript online: 24 JUL 2013 11:11AM EST
- Manuscript Accepted: 17 JUL 2013
- Manuscript Received: 5 APR 2013
- European Union TECHGENE. Grant Number: Health-F5-2009-223143
- GEUVADIS. Grant Number: Health-F7-2010-261123
- European Research Council. Grant Number: DENOVO 281964
- copy number variation;
- whole exome sequencing;
Copy number variation (CNV) is a common source of genetic variation that has been implicated in many genomic disorders. This has resulted in the widespread application of genomic microarrays as a first-tier diagnostic tool for CNV detection. More recently, whole-exome sequencing (WES) has been proven successful for the detection of clinically relevant point mutations and small insertion–deletions exome wide. We evaluate the utility of short-read WES (SOLiD 5500xl) to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth analysis of WES data; a heterozygous single-exon deletion remained undetected by all algorithms evaluated. Although the detection power of WES for small CNVs currently does not match that of high-resolution microarray platforms, we show that the majority (88%) of rare coding CNVs containing three or more exons are successfully identified by WES. These results show that the CNV detection resolution of WES is comparable to that of medium-resolution genomic microarrays commonly used as clinical assays. The combined detection of point mutations, indels, and CNVs makes WES a very attractive first-tier diagnostic test for genetically heterogeneous disorders.